Polymorphic forms of RAD1901-2HCL

ABSTRACT

Various polymorphic forms of RAD1901-2HCl, including three crystalline and amorphous forms, are prepared and characterized. Uses of the various polymorphic forms of RAD1901-2HCl for cancer treatment are also disclosed.

PRIORITY CLAIM

This application is a Divisional Application of U.S. patent applicationSer. No. 15/863,850, filed Jan. 5, 2018, now U.S. Pat. No. 10,385,008,which claims the benefit under 35 U.S.C. § 119 of U.S. ProvisionalPatent Application No. 62/442,921, filed Jan. 5, 2017. The entirecontents of which the aforementioned applications are hereby bothincorporated by reference herein in their entirety, including drawings.

BACKGROUND

RAD1901 is a selective estrogen receptor down-regulator/degrader, orSERD, that crosses the blood-brain barrier and is particularly usefulfor the treatment of metastatic breast cancer. RAD1901 has been shown tobind with good selectivity to the estrogen receptor (ER) and to haveboth estrogen-like and estrogen-antagonistic effect in differenttissues. In many cancers, hormones, like estrogen, stimulate tumorgrowth, and thus a desired therapeutic goal is to block thisestrogen-dependent growth while inducing apoptosis of the cancer cells.SERDs have the potential to be an emerging class of endocrine therapiesthat could directly induce ER degradation, thus potentially enablingthem to remove the estrogen growth signal in ER-dependent tumors withoutallowing ligand-independent resistance to develop.

SUMMARY OF THE INVENTION

Various polymorphic forms of RAD1901-2HCl are disclosed herein, alongwith pharmaceutical compositions thereof, preparation methods thereof,and uses thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

This patent or application contains at least one drawing executed incolor. Copies of this patent or application with color drawing(s) willbe provided by the Office upon request and payment of the necessaryfees.

FIG. 1: Conversion among Forms 1, 2, and 3 of RAD1901-2HCl.

FIG. 2A: RP-HPLC Chromatogram of Sample 1 collected at 255 nm.

FIG. 2B: ¹H NMR of Sample 1 collected in d₆-DMSO.

FIG. 3A: RP-HPLC Chromatogram of Sample 2 collected at 255 nm.

FIG. 3B: ¹H NMR of Sample 2 collected in d₆-DMSO.

FIG. 4A: XRPD diffraction pattern of Sample 1 at ambient RH (e.g.,40-65% RH).

FIG. 4B: Overlay of XRPD patterns obtained for Sample 1 pre-(bottom) andpost-storage (top) at elevated condition analysis.

FIG. 4C: Overlay of VH-XRPD patterns of Sample 1 collected at varied RH.

FIG. 4D: Overlay of XRPD patterns obtained for Sample 1 pre-(bottom) andpost-(top) GVS (uptake 0-90% RH) analysis.

FIG. 4E: Overlay of XRPD patterns obtained for Sample 1 pre-(Sample 1)and post-GVS (HighRH_Desorp_3 and HighRH methods).

FIG. 4F: Overlay of XRPD patterns obtained for Sample 1 pre- andpost-GVS (HighRH_Desorp_3's 1 cycle and HighRH_Double_Cycle's 2 cycles),and post storage at 25° C./97% RH.

FIG. 4G: XRPD diffraction pattern of Sample 1 at 0% RH.

FIG. 4H: Overlay of XRPD diffraction pattern of Forms 1-3.

FIG. 5A: XRPD patterns obtained for Sample 2.

FIG. 5B: Overlay of XRPD patterns obtained for Sample 2 and post-storageat elevated condition analysis.

FIG. 5C: Overlay of XRPD patterns obtained for Sample 1 (top) and Sample2 (bottom 2 plots) post-storage at elevated condition analysis.

FIG. 5D: Overlay of VT-XRPD patterns of Sample 2 collected upon heatingto 200° C. and Sample 1.

FIG. 5E: Overlay of VH-XRPD patterns of Sample 2 collected at high RH(>90%) and Sample 1 post storage at high RH.

FIG. 5F: Overlay of VH-XRPD patterns of Sample 2 collected at drycondition (0% RH).

FIG. 5G: Overlay of XRPD patterns obtained for Sample 2 pre- andpost-GVS (uptake 0-90% RH).

FIG. 5H: XRPD patterns obtained for Sample 2 at 0% RH (Form 2).

FIG. 5I: XRPD patterns obtained for Sample 2 at 92% RH (Form 3).

FIG. 6A: GVS Isotherm Plot for Sample 1 collected from 0 to 90% RH.

FIG. 6B: GVS Kinetic Plot for Sample 1 collected from 0 to 90% RH.

FIG. 6C: GVS Isotherm Plot for Sample 1 collected from 40 to 95% RH withGVS method HighRH.

FIG. 6D: GVS Kinetic Plot for Sample 1 collected from 40 to 95% RH withGVS method HighRH.

FIG. 6E: GVS Isotherm Plot for Sample 1 collected over a single cyclewith GVS method HighRH_Desorp_3.

FIG. 6F: GVS Kinetic Plot for Sample 1 collected over a single cyclewith GVS method HighRH_Desorp_3

FIG. 6G: GVS Isotherm Plot for Sample 1 collected over a double cyclewith GVS method HighRH_DoubleCycle_2.

FIG. 6H: GVS Kinetic Plot for Sample 1 collected over a double cyclewith GVS method HighRH_DoubleCycle_2.

FIG. 7A: GVS Isotherm Plot for Sample 2 collected from 0 to 90% RH.

FIG. 7B: GVS Kinetic Plot for Sample 2 collected from 0 to 90% RH.

FIG. 8: Thermal analysis of Sample 1 by TGA (top) and DSC (bottom).

FIG. 9: Thermal analysis of Sample 2 by TGA (top) and DSC (bottom).

FIG. 10A: PLM images of Sample 1.

FIG. 10B: PLM images of crystals isolated from solubility assessment ofSample 1, produced platelet crystals upon cooling in methanol.

FIG. 11: PLM images of Sample 2.

FIG. 12A: SEM images of Sample 1 (295×).

FIG. 12B: SEM images of Sample 1 (1050×).

FIG. 12C: SEM images of Sample 1 (5100×).

FIG. 13A: SEM images of Sample 2 (730×).

FIG. 13B: SEM images of Sample 2 (1650×).

FIG. 13C: SEM images of Sample 2 (3400×).

FIG. 14A: Overlay of XRPD patterns obtained from the polymorph screen oncrystalline Sample 1, which are substantially consistent with Form 1.

FIG. 14B: Overlay of XRPD patterns obtained from the polymorph screen oncrystalline Sample 1, which are substantially consistent with Form 1.

FIG. 14C: Overlay of XRPD patterns obtained from the polymorph screen oncrystalline Sample 1, which are substantially consistent with Form 3.

FIG. 15A: Overlay of XRPD patterns obtained for Sample 1 pre- andpost-lyophilisation in water or t-butanol/water.

FIG. 15B: Overlay of XRPD patterns obtained for samples obtained bylyophilization if Sample 1 from water or t-butanol/water and crystallinesamples of Sample 1 post-storage at 25° C./97% RH.

FIG. 15C: Overlay of XRPD patterns obtained for samples obtained bylyophilization from water or t-butanol/water of Sample 1 post-storage at25° C./97% RH and 40° C./97% RH.

FIG. 16: ¹H NMR spectra of Sample 1 pre- and post-lyophilisation inwater or t-butanol/water.

FIG. 17A: DSC analysis of samples of Sample 1 obtained by lyophilizationfrom water (solid line) or t-butanol/water (dashed line).

FIG. 17B: TGA analysis of samples of Sample 1 obtained by lyophilizationfrom water (solid line) or t-butanol/water (dashed line).

FIG. 17C: mDSC analysis of a sample of Sample 1 obtained bylyophilization from water (solid line).

FIG. 18A: Overlay of XRPD patterns obtained from the polymorph screen onSample 1 obtained by lyophilization from nitromethane, acetonitrile,THF, ethanol, or propan-1-ol, which are substantially consistent with(anhydrous) Form 1.

FIG. 18B: Overlay of XRPD patterns obtained from the polymorph screen onSample 1 obtained by lyophilization from dichloromethane (DCM), toluene,methyl isobutyl ketone (MIBK), isopropyl acetate, ethyl acetate orpropyl acetate, which are substantially consistent with Form 3 (Sample2, 90% RH) or a mixture of Form 2 and Form 3 (sample 2 post 25/97).

FIG. 18C: Overlay of XRPD patterns obtained from the polymorph screen onSample 1 obtained by lyophilization from 10% water/THF, 10% water/IPA,10% water/EtOH, water, dimethoxyethane, or methanol, which aresubstantially consistent with Form 3 (hydrate, Sample 2, 90% RH) or amixture of Form 2 (anhydrous) and Form 3 (sample 2 post 25/97).

FIG. 18D: Overlay of XRPD patterns obtained from the polymorph screen onSample 1 obtained by lyophilization from 1,4-dioxane, t-butyl methylether (TBME), acetone, methyl ethyl ketone (MEK), propan-2-ol, orn-heptane, which are too poorly crystalline to assign polymorph, butappear to be Form 1 or a mixture of Form 2 and Form 3 (sample 2 post25/97).

FIG. 19A: PLM images of crystals obtained during polymorph screensprepared by cooling a lyophilized sample of Sample 1-methanol.

FIG. 19B: PLM images of crystals obtained during polymorph screensprepared by maturation of a lyophilized sample of Sample 1 in water.

FIG. 19C: PLM images of crystals obtained during polymorph screensprepared by maturation of a lyophilized sample of Sample 1 innitromethane.

FIG. 20A: Overlay of XRPD patterns of samples prepared by maturation ofa lyophilized sample of Sample 1 in different water/ethanol solventmixtures, which are substantially consistent with Form 1 or Form 3(hydrate) (sample 1 post 25/97).

FIG. 20B: Overlay of XRPD patterns of samples prepared by maturation ofa lyophilized sample of Sample 1 in different water/methanol solventmixtures, which are substantially consistent with Form 2 or Form 3(hydrate) (sample 1 post 25/97).

FIG. 20C: Overlay of XRPD patterns of samples prepared by maturation ofa lyophilized sample of Sample 1 in anhydrous or water-saturated ethylacetate, which are substantially consistent with Form 1 or Form 3(sample 1 post 25/97).

DETAILED DESCRIPTION

-   I. Polymorphic Forms of RAD1901-2HCl

As set forth in the Examples section below, three crystalline andamorphous forms of RAD1901-2HCl were prepared and characterized.

The definitions provided herein are meant to clarify, but not limit, theterms defined. If a term used herein is not specifically defined, suchterm should not be considered indefinite. Rather, terms are used withintheir accepted meanings.

As used herein, RAD1901-2HCl refers to a salt form wherein the molarratio of RAD1901 and HCl is approximately 2, e.g., from about 1.7 toabout 2.1, or from 1.8 to about 2.0. Small changes in the amount ofassayed HCl can be attributed to, without limitation, measurementvariability and loss of small amounts of HCl through storage and/orprocessing.

As used herein, “crystalline” refers to a solid having a highly regularchemical structure. In particular, a crystalline free base or salt formmay be produced as one or more single crystalline forms. For thepurposes of this application, the terms “crystalline form”, “singlecrystalline form” and “polymorph” are synonymous; the terms distinguishbetween crystals that have different properties (e.g., different XRPDpatterns and/or different DSC scan results). The term “polymorph”includes pseudopolymorphs, which are typically different solvates of amaterial, and thus their properties differ from one another. Thus, eachdistinct polymorph and pseudopolymorph of a free base or salt form isconsidered to be a distinct single crystalline form herein.

The term “substantially crystalline” refers to forms that may be atleast a particular weight percent crystalline. Particular weightpercentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,99.9%, or any percentage between 10% and 100%. In some embodiments,substantially crystalline refers to a free base or salt form that is atleast 70% crystalline. In other embodiments, substantially crystallinerefers to a free base or salt form that is at least 90% crystalline.

As used herein, “amorphous” refers to a solid material comprisingnon-crystalline materials. In certain embodiments, an amorphous sampleof a material may be prepared by lyophilization of a mixture of thematerial with a solvent, wherein the mixture may be homogeneous (e.g.,solution) or heterogeneous (e.g., a slurry).

The term “substantially free” refers to forms and compositions that maybe at least a particular weight percent free of impurities and/orcrystalline compound. Particular weight percentages are 60%, 70%, 75%,80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, 99.9%, or any percentage between 60% and 100% free ofimpurities and/or crystalline compound. In some embodiments,substantially free refers to a free base or salt form that is at least70% pure. In other embodiments, substantially crystalline refers to afree base or salt form that is at least 90% pure. In other embodiments,substantially free of crystalline compound refers to a compositionhaving less than about 30%, less than about 20%, less than about 15%,less than about 10%, less than about 5%, less than about 1% ofcrystalline compound.

The term “hydrate” is a solvate wherein the solvent molecule is H₂O thatis present in a defined stoichiometric or non-stoichiometric amount.Stoichiometric solvates may, for example, include hemihydrate,monohydrate, dihydrate, or trihydrate forms, among others.Non-stoichiometric solvates may include, for example, channel hydrates,including where water content may change depending on humidity of theenvironment.

The term “solvate or solvated” means a physical association of acompound, including a crystalline form thereof, of this invention withone or more solvent molecules. This physical association includeshydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvateor solvated” encompasses both solution-phase and isolable solvates.Representative solvates include, for example, a hydrate, ethanolates ora methanolate.

The term “stable” in the context of a polymorphic form disclosed hereinrefers to the stability of the polymorphic form relative to heat and/orhumidity.

The relationship among the three crystalline forms of RAD1901 isprovided in FIG. 1.

As used herein, crystalline forms of RAD1901-2HCl are referred to asForms 1, 2, and 3, respectively. Forms 1 and 2 are anhydrous forms ofRAD1901-2HCl, and Form 3 is a hydrated form of RAD1901-2HCl. Forms 1, 2,and 3 showed different X-ray powder diffraction (XRPD) patterns.

Sample 1 refers to an initially uncharacterized batch of RAD1901-2HClthat was subsequently determined to be predominately Form 1. Sample 2refers to an initially uncharacterized batch of RAD1901-2HCl that wassubsequently determined to be a mixture of Form 2 and Form 3

GVS experiments showed that Form 2 was hygroscopic with a mass uptakefrom 0-40% RH, and the mass uptake plateaued above 40% RH. Thus, anequilibrium existed between the anhydrous Form 2 and hydrate Form 3 atnear ambient RH. Anhydrous Form 1 demonstrated low hygroscopicitybetween 0-90% RH, and started converting to the hydrate Form 3 at above90% RH.

In many embodiments disclosed herein, RAD1901-2HCl is disclosed ashaving a crystalline structure.

In certain embodiments, crystalline structures in this disclosure can beidentified by having one or more characteristics peaks in an XRPDspectrum, as disclosed herein.

In some embodiments, crystalline structures in this disclosure have oneor more characteristics endothermic peaks in differential scanningcalorimetry, as disclosed herein.

In certain embodiments, methods of preparing and/or interconverting oneor more crystalline forms of RAD1901-2HCl are provided. Furtherembodiments describe the conversion to, and preservation of acrystalline form of RAD1901-2HCl that has desired stability underexpected storage conditions.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at 7.1 degrees 2θ±0.2 degrees 2θ at about relativehumidity 0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising apeak, in terms of 20, at 7.1 degrees 2θ±0.2 degrees 20, and/or 14.3degrees 2θ±0.2 degree 2θ at about relative humidity 0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast two peaks, in terms of 2-theta, selected from the group consistingof 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree 2θ and 18.3degrees 2θ±0.2 degree 2θ at about relative humidity 0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast three peaks, in terms of 2-theta, selected from the groupconsisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ and12.0 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%, e.g., Form1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast four peaks, in terms of 2-theta, selected from the groupconsisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ and 18.9 degrees2θ±0.2 degree 2θ, at about relative humidity 0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast five peaks, in terms of 2-theta, selected from the groupconsisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ and 11.0 degrees 2θ±0.2degree 2θ, at about relative humidity 0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast seven peaks, in terms of 2-theta, selected from the groupconsisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2degree 2θ, and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast eight peaks, in terms of 2-theta, selected from the groupconsisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2degree 2θ, and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-Ray powder diffraction pattern comprising atleast nine peaks, in terms of 2-theta, selected from the groupconsisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2 degree2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2degree 2θ, and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising thepeaks, in terms of 2-theta, of 7.1 degrees 2θ±0.2 degree 2θ, 14.3degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ,11.0 degrees 2θ±0.2 degree 2θ, and 16.2 degrees 2θ±0.2 degree 2θ, atabout relative humidity 0%, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form (Form 1)having an X-ray powder diffraction pattern substantially as shown inFIG. 4G at about relative humidity 0%.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having a differential scanning calorimetry (DSC)thermogram displaying a melting onset at 218.2° C. and an endothermicpeak at 232.1° C., e.g., Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having a differential scanning calorimetry (DSC)thermogram substantially as shown in the bottom graph of FIG. 8, e.g.,Form 1.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having a thermogravimetric analysis (TGA) substantially asshown in the top graph of FIG. 8, e.g., Form 1.

Certain embodiments disclosed herein provide a solid form of RAD1901 asdisclosed herein (e.g., Form 1) wherein said solid form comprises atleast 1% w/w of a total sample of RAD1901-2HCl.

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 5% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 10% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 25% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 50% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 90% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 95% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 98% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a composition comprisingRAD1901 wherein at least 99% w/w of the total amount of RAD1901 is asolid form of RAD1901 as disclosed herein (e.g., Form 1).

Certain embodiments disclosed herein provide a pharmaceuticalcomposition comprising Form 1 in any of its specified embodiments andone or more pharmaceutically acceptable excipients.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl having an X-Ray powder diffraction pattern comprising apeak, in terms of 2-theta, at 6.3 degrees 2θ±0.2 degree 2θ at aboutrelative humidity 0%, e.g., Form 2.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising apeak, in terms of 2-theta, at 6.3 degrees 2θ±0.2 degree 2θ, and/or 12.5degrees 2θ±0.2 degree 2θ at about relative humidity 0%, e.g., Form 2.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising atleast two peaks, in terms of 2-theta, selected from the group consistingof 6.3 degrees 2θ±0.2 degree 2θ, 12.5 degrees 2θ±0.2 degree 2θ, and 15.4degrees 2θ±0.2 degree 2θ, at about relative humidity 0%, e.g., Form 2.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising atleast two peaks, in terms of 2-theta, selected from the group consistingof 6.3 degrees 2θ±0.2 degree 2θ, 12.5 degrees 2θ±0.2 degree 2θ, and 15.4degrees 2θ±0.2 degree 2θ, at about relative humidity 0%, e.g., Form 2.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising atleast three peaks, in terms of 2-theta, selected from the groupconsisting of 6.3 degrees 2θ±0.2 degree 2θ, 12.5 degrees 2θ±0.2 degree2θ, 15.4 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, and13.4 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%, e.g., Form2.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern substantiallyas shown in FIG. 5H at about relative humidity 0%, e.g., Form 2.

Certain embodiments disclosed herein provide a pharmaceuticalcomposition comprising a solid form of RAD1901-2HCl disclosed herein(e.g., Form 2), and one or more pharmaceutically acceptable excipients.

In some embodiments, a solid form RAD1901-2HCl is a crystalline mixturecomprising less than 1% Form 2.

In certain embodiments, a solid form RAD1901-2HCl is a crystallinemixture comprising more than 0.1% of Form 2 but less than 2%.

In some embodiments, a solid form RAD1901-2HCl comprises at least 10%Form 2.

In some embodiments, a solid form RAD1901-2HCl comprises at least 25%Form 2.

In some embodiments, a solid form RAD1901-2HCl comprises at least 50%Form 2.

In some embodiments, a solid form RAD1901-2HCl comprises at least 75%Form 2.

In some embodiments, a solid form RAD1901-2HCl comprises at least 95%Form 2.

In some embodiments, a solid form RAD1901-2HCl comprises at least 97%Form 2.

In some embodiments, a solid form RAD1901-2HCl comprises at least 99%Form 2.

Certain embodiments disclosed herein provide a solid, hydrated form ofRAD1901-2HCl, e.g., Form 3. In some embodiments the solid hydrated formof RAD1901-2HCl is a dihydrate.

Certain embodiments disclosed herein provide a solid, hydrated form ofRAD1901-2HCl having an X-Ray powder diffraction comprising a peak, interms of 2-theta, at 5.8 degrees 2θ±0.2 degree 2θ at about relative 92%,e.g., Form 3.

Certain embodiments disclosed herein provide a solid hydrated form ofRAD901-2HCl having an X-ray powder diffraction pattern comprising apeak, in terms of 2-theta, at 5.8 degrees 2θ±0.2 degree 2θ, and/or 21.3degrees 2θ±0.2 degree 2θ, at about relative humidity 92%, e.g., Form 3.

Certain embodiments disclosed herein provide a solid hydrated form ofRAD1901-2HCl having an X-ray powder diffraction pattern comprising atleast two peaks, in terms of 2-theta, selected from the group consistingof 5.8 degrees 2θ±0.2 degree 2θ, 21.3 degrees 2θ±0.2 degree 2θ, and 24.8degrees 2θ±0.2 degree 2θ, at about relative humidity 92%, e.g., Form 3.

Certain embodiments disclosed herein provide a solid hydrated form ofRAD1901-2HCl having an X-Ray powder diffraction pattern comprising atleast three peaks, in terms of 2-theta, selected from the groupconsisting of 5.8 degrees 2θ±0.2 degree 2θ, 21.3 degrees 2θ±0.2 degree2θ, 24.8 degrees 2θ±0.2 degree 2θ, 23.3 degrees 2θ±0.2 degree 2θ, and9.5 degrees 2θ±0.2 degree 2θ, at about relative humidity 92%, e.g., Form3.

Certain embodiments disclosed herein provide a solid hydrated form ofRAD1901-2HCl having an X-Ray powder diffraction pattern comprising atleast four peaks, in terms of 2-theta, selected from the groupconsisting of 5.8 degrees 2θ±0.2 degree 2θ, 21.3 degrees 2θ±0.2 degree2θ, 24.8 degrees 2θ±0.2 degree 2θ, 23.3 degrees 2θ±0.2 degree 2θ, and9.5 degrees 2θ±0.2 degree 2θ, at about relative humidity 92%, e.g., Form3.

Certain embodiments disclosed herein provide a solid form ofRAD1901-2HCl that is amorphous.

Certain embodiments disclosed herein provide one or more crystallineand/or amorphous form of RAD1901-2HCl dispersed into a matrix.

Certain embodiments are disclosed comprising a dosage form ofRAD1901-2HCl comprising 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg,or 600 mg of RAD1901-2HCl in one or more crystalline and/or amorphousforms, wherein said one or more crystalline and/or amorphous forms aredispersed in a solid or liquid matrix.

II. Pharmaceutical compositions and/or formulas of Polymorphic Forms ofRAD1901-2HCl

Provided herein are pharmaceutical compositions comprising one or morepolymorphous and/or amorphous forms of RAD1901-2HCl disclosed herein,and a physiologically acceptable carrier (also referred to as apharmaceutically acceptable carrier or solution or diluent). Suchcarriers and solutions include pharmaceutically acceptable salts andsolvates of compounds used in the methods of the instant invention, andmixtures comprising two or more of such compounds, pharmaceuticallyacceptable salts of the compounds and pharmaceutically acceptablesolvates of the compounds. Such compositions are prepared in accordancewith acceptable pharmaceutical procedures such as described inRemington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R.Gennaro, Mack Publishing Company, Easton, Pa. (1985), which isincorporated herein by reference.

The term “pharmaceutically acceptable carrier” refers to a carrier thatdoes not cause an allergic reaction or other untoward effect in asubject to whom it is administered and are compatible with the otheringredients in the formulation. Pharmaceutically acceptable carriersinclude, for example, pharmaceutical diluents, excipients or carrierssuitably selected with respect to the intended form of administration,and consistent with conventional pharmaceutical practices. For example,solid carriers/diluents include, but are not limited to, a gum, a starch(e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.,microcrystalline cellulose), an acrylate (e.g., polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.Pharmaceutically acceptable carriers may further comprise minor amountsof auxiliary substances such as wetting or emulsifying agents,preservatives or buffers, which enhance the shelf life or effectivenessof the therapeutic agent.

The term “patient” refers to a human subject.

The one or more polymorphous and/or amorphous forms of RAD1901-2HCldisclosed herein and pharmaceutical composition thereof may beformulated into unit dosage forms, meaning physically discrete unitssuitable as unitary dosage for subjects undergoing treatment, with eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, optionally in associationwith a suitable pharmaceutical carrier. The unit dosage form can be fora single daily dose or one of multiple daily doses (e.g., about 1 to 4or more times per day). When multiple daily doses are used, the unitdosage form can be the same or different for each dose. In certainembodiments, the compounds may be formulated for controlled release.

The one or more polymorphous and/or amorphous forms of RAD1901-2HCldisclosed herein and pharmaceutical composition thereof may beformulated according to any available conventional method. Examples ofpreferred dosage forms include a tablet, a powder, a subtle granule, agranule, a coated tablet, a capsule, a syrup, a troche, and the like. Inthe formulation, generally used additives such as a diluent, a binder,an disintegrant, a lubricant, a colorant, a flavoring agent, and ifnecessary, a stabilizer, an emulsifier, an absorption enhancer, asurfactant, a pH adjuster, an antiseptic, an antioxidant and the likecan be used. In addition, the formulation is also carried out bycombining compositions that are generally used as a raw material forpharmaceutical formulation, according to the conventional methods.Examples of these compositions include, for example, (1) an oil such asa soybean oil, a beef tallow and synthetic glyceride; (2) hydrocarbonsuch as liquid paraffin, squalane and solid paraffin; (3) ester oil suchas octyldodecyl myristic acid and isopropyl myristic acid; (4) higheralcohol such as cetostearyl alcohol and behenyl alcohol; (5) a siliconresin; (6) a silicon oil; (7) a surfactant such as polyoxyethylene fattyacid ester, sorbitan fatty acid ester, glycerin fatty acid ester,polyoxyethylene sorbitan fatty acid ester, a solid polyoxyethylenecastor oil and polyoxyethylene polyoxypropylene block co-polymer; (8)water soluble macromolecule such as hydroxyethyl cellulose, polyacrylicacid, carboxyvinyl polymer, polyethyleneglycol, polyvinylpyrrolidone andmethylcellulose; (9) lower alcohol such as ethanol and isopropanol; (10)multivalent alcohol such as glycerin, propyleneglycol, dipropyleneglycoland sorbitol; (11) a sugar such as glucose and cane sugar; (12) aninorganic powder such as anhydrous silicic acid, aluminum magnesiumsilicate and aluminum silicate; (13) purified water, and the like.Additives for use in the above formulations may include, for example, 1)lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystallinecellulose and silicon dioxide as the diluent; 2) polyvinyl alcohol,polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic,tragacanth, gelatin, shellac, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropyleneglycol-poly oxyethylene-block co-polymer, meglumine, calcium citrate,dextrin, pectin and the like as the binder; 3) starch, agar, gelatinpowder, crystalline cellulose, calcium carbonate, sodium bicarbonate,calcium citrate, dextrin, pectic, carboxymethylcellulose/calcium and thelike as the disintegrant; 4) magnesium stearate, talc,polyethyleneglycol, silica, condensed plant oil and the like as thelubricant; 5) any colorants whose addition is pharmaceuticallyacceptable is adequate as the colorant; 6) cocoa powder, menthol,aromatizer, peppermint oil, cinnamon powder as the flavoring agent; 7)antioxidants whose addition is pharmaceutically accepted such asascorbic acid or alpha-tophenol.

Some embodiments disclosed herein provide a pharmaceutical dosage formcomprising RAD1901-2HCl Form 1 in an amount of 50 gm, 100 mg, 200 mg,300 mg, 400 mg, 500 mg, or 600 mg.

Certain embodiments disclosed herein provide a drug dosage form as atablet comprising 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600mg RAD1901-2HCl crystalline Form 1. In certain embodiments, at least80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least99.5% of RAD1901 in the table is RAD1901-2HCl crystalline Form 1.

Certain embodiments disclosed herein provide a pharmaceuticalcomposition comprising 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or600 mg of a solid form of RAD1901-2HCl disclosed herein (e.g.,comprising Form 2 and/or Form 3), and one or more pharmaceuticallyacceptable excipients.

In certain embodiments, a pharmaceutical dosage form comprises Form 2 asdisclosed herein.

-   III. Use of the Polymorphic Forms of RAD1901-2HCl

Provided herein are methods of treating and/or preventing one or moreconditions of a subject that can benefit from administration of RAD1901,the methods comprise administering to the subject with therapeuticallyeffective amount of one or more polymorphic forms of RAD1901-2HCldisclosed herein, or a pharmaceutical composition thereof.

In certain embodiments, the one or more conditions treated/prevented bythe methods disclosed herein are breast, uterus, and ovary tumors and/orcancers having overexpression of estrogen receptors, and metastaticcancer and/or tumor. In certain embodiments, the cancer and/or tumortreated in the methods disclosed herein are resistant ER-driven cancersor tumors, (e.g. having mutant ER binding domains (e.g. ERα comprisingone or more mutations including, but not limited to, Y537X₁ wherein X₁is S, N, or C, D538G, L536X₂ wherein X₂ is R or Q, P535H, V534E, S463P,V392I, E380Q and combinations thereof), overexpressors of the ERs ortumor and/or cancer proliferation becomes ligand independent, or tumorsand/or cancers that progress after endocrinological treatment, such aswith treatment of SERD (e.g., fulvestrant, TAS-108 (SR16234), ZK191703,RU58668, GDC-0810 (ARN-810), GW5638/DPC974, SRN-927, and AZD9496),aromatase inhibitor (e.g., anastrozole, exemestane, and letrozole),selective estrogen receptor modulators (e.g., tamoxifen, raloxifene,lasofoxifene, and/or toremifene), Her2 inhibitors (e.g., trastuzumab,lapatinib, ado-trastuzumab emtansine, and/or pertuzumab), chemo therapy(e.g., abraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil,ellence, fluorouracil, gemzar, helaven, lxempra, methotrexate,mitomycin, micoxantrone, navelbine, taxol, taxotere, thiotepa,vincristine, and xeloda), angiogenesis inhibitor (e.g., bevacizumab),cdk4/6 inhibitors, m-TOR inhibitors and/or rituximab.

Provided herein are methods of modulating estrogen receptors of asubject, the methods comprise administering to the subject withtherapeutically effective amount of one or more polymorphic forms ofRAD1901-2HCl disclosed herein, or a pharmaceutical composition thereof;and the one or more polymorphic forms of RAD1901-2HCl disclosed hereindemonstrate an estrogen-like action in the central nervous system, bonetissue and lipid metabolism, and/or estrogen antagonism in areproductive organ and a mammary gland.

A therapeutically effective amount of the one of more polymorphic formsof RAD1901-2HCl for use in the methods disclosed herein is an amountthat, when administered over a particular time interval, results inachievement of one or more therapeutic benchmarks (e.g., slowing orhalting of tumor growth, cessation of symptoms, etc.). The skilledartisan can readily determine this amount, on either an individualsubject basis (e.g., the amount of the one of more polymorphic forms ofRAD1901-2HCl necessary to achieve a particular therapeutic benchmark inthe subject being treated) or a population basis (e.g., the amount ofthe one of more polymorphic forms of RAD1901-2HCl necessary to achieve aparticular therapeutic benchmark in the average subject from a givenpopulation). Ideally, the therapeutically effective amount does notexceed the maximum tolerated dosage at which 50% or more of treatedsubjects experience nausea or other toxicity reactions that preventfurther drug administrations. A therapeutically effective amount mayvary for a subject depending on a variety of factors, including varietyand extent of the symptoms, sex, age, body weight, or general health ofthe subject, administration mode and salt or solvate type, variation insusceptibility to the drug, the specific type of the disease, and thelike.

The one of more polymorphic forms of RAD1901-2HCl or the pharmaceuticalcomposition thereof for use in the presently disclosed methods may beadministered to a subject one time or multiple times. In thoseembodiments wherein the compounds are administered multiple times, theymay be administered at a set interval, e.g., daily, every other day,weekly, or monthly. Alternatively, they can be administered at anirregular interval, for example on an as-needed basis based on symptoms,patient health, and the like.

Some embodiments disclosed herein provide a method of treating ER+breast cancer comprising a daily administration of 400 mg ofRAD1901-2HCl crystalline Form 1 in a dosage form wherein said dosageform is a tablet or capsule and said administration is oral.

Some embodiments disclosed herein provide a method of treating ER+breast cancer in a subject, wherein: the ER+ breast cancer is resistantto one or more endocrinological therapies or the subject has progressedafter prior treatment with one or more endocrinological therapies; thetreatment comprises a daily administration of 400 mg of RAD1901-2HClcrystalline Form 1 in a dosage form; and the dosage form is a tablet orcapsule and said administration is oral.

Some embodiments disclosed herein provide a method of treating ER+breast cancer in a subject wherein: the ER+ breast cancer is resistantto one or more endocrinological therapies or the subject has progressedafter prior treatment with one or more endocrinological therapies; thetreatment comprises a first administration of 400 mg daily ofRAD1901-2HCl crystalline Form 1 in a dosage form; the dosage form is atablet or capsule; the administration is oral; the administration ofRAD1901-2HCl crystalline Form 1 is in combination with a secondadministration of a cdk4/6 inhibitor and/or an m-TOR inhibitor; and thesecond administration is an administration method suitable for thecdk4/6 inhibitor and/or m-TOR inhibitor.

Some embodiments disclosed herein provide a method of treating ER+breast cancer in a subject wherein: the ER+ breast cancer is resistantto one or more endocrinological therapies or the subject has progressedafter prior treatment with one or more endocrinological therapies; thetreatment comprises a first administration of 400 mg daily ofRAD1901-2HCl crystalline Form 1 in a dosage form; the dosage form is atablet or capsule; the administration is oral; and the firstadministrati is in combination with a second administration ofpalbociclib, ribociclib, abemaciclib and/or everolimus.

Some embodiments disclosed herein provide a method of treating ER+breast cancer in a subject wherein: the ER+ breast cancer is resistantto one or more cdk4/6 inhibitors and/or m-TOR inhibitors; the treatmentcomprises a daily administration of 400 mg of RAD1901-2HCl crystallineForm 1 in a dosage form; the dosage form is a tablet or capsule; and theadministration is oral.

Certain embodiments disclosed herein provide a method of treating breastcancer comprising an administration to a subject in need thereof acrystalline form of RAD1901-2HCl (e.g., Form 1 as disclosed herein). Insome embodiments, the breast cancer is ER+.

Certain embodiments disclosed herein provide a method of treatingovarian cancer comprising an administration to a subject in need thereofRAD1901-2HCl (Form 1). In some embodiments, the ovarian cancer is ER+.

In some embodiments, provided herein is a method of treating ER+ breastcancer comprising an administration of a dosage form comprising one ormore crystalline forms of RAD1901-2HCl as disclosed herein.

In some embodiments, the manufacture of a medicament useful for treatinga subject in need with RAD1901-2HCl is provided herein, wherein themedicament comprises one or more crystalline and/or amorphous forms ofRAD1901-2HCl as disclosed herein.

-   IV. Preparation of the Polymorphic Forms of RAD1901-2HCl

Provided herein are methods for preparing Forms 1, 2 and 3 ofRAD1901-2HCl disclosed herein.

In certain embodiments, RAD1901-2HCl can be prepared by treating aRAD1901 solution in an organic solvent (e.g., EtOH, EtOAc, and mixturesthereof) with at least 2 eq. of HCl (e.g., in EtOH). In certainembodiments, a RAD1901-2HCl solution can be further concentrated,treated with an organic solvent (e.g., EtOAc), and filtered to provideRAD1901 as its bis-HCl salt, suitable for further processing accordingto the methods of form conversion provided in this disclosure.

In certain embodiments, Form 1 can be prepared by treating RAD1901-2HClwith an organic solvent substantially free of methanol (e.g., less than5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than0.5% of the organic solvent is methanol) with relatively low watercontent (e.g., less than 5% v/v). In certain embodiments, Form 1 can beprepared by treating RAD1901-2HCl with an organic solvent (e.g., EtOH,etc.) with relatively low water content (e.g., less than 5% v/v) andthen with another organic solvent in which RAD1901-2HCl has a lowersolubility (e.g., esters such as EtOAc, etc.). As used herein, unlessotherwise specified, an organic solvent may be a single organic solventor a mixture of multiple organic solvents.

Certain embodiments disclosed herein provide methods of preparing Form 1of RAD1901-2HCl comprising precipitating from a solution comprisingRAD1901-2HCl and a solvent, or slurrying RAD1901-2HCl in a solvent,wherein the solvent comprises an organic solvent substantially free ofmethanol, and the content of water is at or below 5% v/v. In someembodiments, the organic solvent is selected from the group consistingof n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, MIBK,MEK, 1-propanol, ethanol, TBME, 1,4-dioxane, toluene,1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile,nitromethane, and mixtures thereof.

In certain embodiments, Form 2, Form 3, or combinations thereof can beprepared by treating RAD1901-2HCl with an organic solvent containingwater and/or methanol. In certain embodiments, Form 2, Form 3, orcombinations thereof can be prepared by treating RAD1901-2HCl with anorganic solvent containing water and/or methanol, and then with anotherorganic solvent in which RAD1901-2HCl has a lower solubility (e.g.,esters such as EtOAc, etc.). Form 3 can be preferably prepared via usingsolvents having a water content of 5% or higher. In certain embodiments,Form 2 can be prepared using MeOH with a water content of about 1% toabout 2%.

In certain embodiments, methods for preparing Form 1 of RAD1901-2HClcomprises heating a composition comprising Form 2, Form 3, orcombinations thereof at a temperature above 175° C. for a period of timesufficient for the conversion at a RH of about 90% or lower, about 85%or lower, about 80% or lower, about 75% or lower, about 70% or lower,about 65% or lower, about 60% or lower, about 55% or lower, about 50% orlower, about 45% or lower, or about 40% or lower.

In certain embodiments, methods of preparing Form 2 of RAD1901-2HClcomprises exposing a composition comprising Form 3 thereof to a RH ofabout 0% for a period of time sufficient for the conversion (e.g., 6 hat 0% RH).

In certain embodiments, methods of preparing Form 3 of RAD1901-2HClcomprises exposing a composition comprising Form 2, Form 3, orcombinations thereof to a RH of about 40% or higher for a period of timesufficient for the conversion (e.g., about 2 weeks at RH 40%).

In certain embodiments, methods of preparing Form 3 of RAD1901-2HClcomprises exposing a composition comprising Form 1 to a RH of about 90%or higher for a period of time sufficient for the conversion (e.g., 1week at 90% RH).

EXAMPLES

-   Instrument and Methodology

A. X-Ray powder Diffraction (XRPD)

Two x-ray diffractometer instruments were used to collect X-raydiffraction patterns as described below.

-   -   A1. Bruker AXS C2 GADDS

X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZstage, laser video microscope for auto-sample positioning and a HiStar2-dimensional area detector. X-ray optics consists of a single Göbelmultilayer mirror coupled with a pinhole collimator of 0.3 mm. A weeklyperformance check was carried out using a certified standard NIST 1976Corundum (flat plate).

The beam divergence, i.e. the effective size of the X-ray beam on thesample, was approximately 4 mm. A θ-θ continuous scan mode was employedwith a sample-detector distance of 20 cm which gave an effective 2θrange of 3.2°-29.7°. Typically, the sample was exposed to the X-ray beamfor 120 seconds. The software used for data collection was GADDS forXP/2000 4.1.43 and the data were analyzed and presented using DiffracPlus EVA v15.0.0.0.

-   -   A1-1) Ambient Conditions

Samples run under ambient conditions were prepared as flat platespecimens using powder as received without grinding. A sample waslightly pressed on a glass slide to obtain a flat surface.

-   -   A1-2) Non-ambient Conditions

Samples run under non-ambient conditions were mounted on a silicon waferwith a heat-conducting compound. The sample was then heated from ambientto the appropriate temperature at 20° C./min and subsequently heldisothermally for 1 minute before data collection was initiated. Thesample was observed to melt during the experiment and recrystallizedupon continued heated above this temperature.

A2. Bruker AXS D8 Advance

X-Ray Powder Diffraction patterns were collected on a Bruker D8diffractometer using Cu Kα radiation (40 kV, 40 mA), θ-2θ goniometer,and divergence of V4 and receiving slits, a Ge monochromator and aLynxeye detector. The instrument was performance checked using acertified Corundum standard (NIST 1976). The software used for datacollection was Diffrac Plus XRD Commander v2.6.1 and the data wereanalyzed and presented using Diffrac Plus EVA v15.0.0.0.

-   -   A2-1) Ambient Conditions

Samples run under ambient conditions as flat plate specimens usingpowder as received. The sample was gently packed into a cavity, cut intopolished, zero-background (510) silicon wafer. The sample was rotated inits own plane during analysis. The data were collected in an angularrange of 2 to 42° 2θ, with a step size of 0.05° 2 θ, and a collectiontime of 0.5 sec/step.

-   -   A2-2) Non-ambient Conditions

Samples run under non-ambient conditions were prepared by gently packinginto a cavity, cut into a silicon wafer to obtain a flat surface andmounted onto a humidity stage with an Ansyco controller and humiditysensor positioned directly next to the sample holder. The data werecollected at 298.15 K with water temperature of 35.0° C., in an angularrange of 3 to 31° 2θ, with a step size of 0.025° 2θ, a collection timeof 2.0 sec/step, and a collection time at each % RH was 41 min 28 sec.

X-Ray Powder Diffraction (XRPD) patterns were collected at variablehumidity values from 0 to 95% RH, based upon the humidity behavior ofeach compound observed during GVS experiments (described herein). Foreach Variable Humidity X-Ray Powder Diffraction (VH-XRPD) experimentperformed, the % RH values selected are provided alongside the relevantexperimental result. Full tables of detailing the % RH value at eachcollection point and the associated delay time at each value areprovided in Tables 10-12.

Unless stated otherwise, listed 2θ values in this disclosure are +/−0.2degrees 2θ.

-   B. Nuclear Magnetic Resonance (NMR): ¹H NMR and ¹³C NMR

NMR spectra were collected on a Bruker 400 MHz instrument equipped withan auto-sampler and controlled by a DRX400 console. Automatedexperiments were acquired using ICON-NMR v4.0.7 running with Topspinv1.3 using the standard Bruker loaded experiments. For non-routinespectroscopy, data were acquired through the use of Topspin alone.Samples were prepared in DMSO-d6. Off-line analysis was carried outusing ACD Spectrus Processor 2014.

-   C. Differential Scanning calorimetry (DSC)

DSC data were collected on a TA Instruments Q2000 equipped with a 50position autosampler. The calibration for thermal capacity was carriedout using sapphire and the calibration for energy and temperature wascarried out using certified indium. Each sample (e.g., 1 mg, 2 mg), in apin-holed aluminum pan, was heated at 10° C./min from 25° C. to 300° C.A purge of dry nitrogen at 50 ml/min was maintained over the sample.Modulated temperature DSC was carried out using an underlying heatingrate of 1 or 2° C./min and temperature modulation parameters of ±0.318or 0.636° C. (amplitude) respectively, every 60 seconds (period).

The instrument control software was Advantage for Q Series v2.8.0.394and Thermal Advantage v5.5.3 and the data were analyzed using UniversalAnalysis v4.5A.

Unless stated otherwise, listed DSC temperatures are +/−3° C.

-   D. Thermo-Gravimetric Analysis (TGA)

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16position autosampler. The instrument was temperature calibrated usingcertified Alumel and Nickel.

Each sample (e.g., 5 mg) was loaded onto a pre-tared aluminum DSC panand heated at 10° C./min from ambient temperature to 300° C. A nitrogenpurge at 60 ml/min was maintained over the sample.

The instrument control software was Advantage for Q Series v2.5.0.256and Thermal Advantage v5.5.3 and the data were analyzed using UniversalAnalysis v4.5A.

-   E. Polarized Light Microscopy (PLM)

Samples were studied on a Nikon SMZ1500 polarized light microscope witha digital video camera connected to a DS Camera control unit DS-L2 forimage capture. A small amount of each sample was placed on a glassslide, mounted in immersion oil, the individual particles beingseparated as well as possible. The sample was viewed with appropriatemagnification and partially polarized light, coupled to a λ false-colorfilter.

-   F. Scanning Electron Microscopy (SEM)

Data were collected on a Phenom Pro Scanning Electron Microscope. Asmall quantity of sample was mounted onto an aluminum stub usingconducting double-sided adhesive tape. A thin layer of gold was appliedusing a sputter coater (20 mA, 120 s).

-   G. Water Determination by Karl Fischer Titration (KF)

The water content of each sample was measured on a Metrohm 874 OvenSample Processor at 200° C. with 851 Titrano Coulometer using HydranalCoulomat AG oven reagent and nitrogen purge. Weighed solid samples wereintroduced into a sealed sample vial. Approx 10 mg of sample was usedper titration and duplicate determinations were made. Data collectionand analysis using Tiamo v2.2.

-   H. Chemical Purity Determination by HPLC

Purity analysis was performed on an Agilent HP1100 series systemequipped with a diode array detector (255 nM with 90 nM bandwidth) andusing ChemStation software vB.04.03. Samples were prepared as 0.4-0.6mg/mL in acetonitrile: water 1:1 solution. HPLC analysis was performedon a Supelco Ascentic Express C18 reversed-phase column (100×4.6 mm, 2.7μm) with gradient elution shown in Table 1 at a flow rate of 2 mL/min.The column temperature was 25° C.; and each sample injection was 2 or 3μL.

TABLE 1 HPLC Gradient Elution % Phase A % Phase B (0.085% Time (min)(0.1% TFA in water) TFA in acetonitrile) 0 95 5 6 5 95 6.2 95 5 8 95 5

-   I. Gravimetric Vapour Sorption (GVS)

Sorption isotherms were obtained using a SMS DVS Intrinsic moisturesorption analyzer, controlled by DVS Intrinsic Control software v1.0.1.2(or v 1.0.1.3). The sample temperature was maintained at 25° C. by theinstrument controls. The humidity was controlled by mixing streams ofdry and wet nitrogen, with a total flow rate of 200 ml/min. The relativehumidity was measured by a calibrated Rotronic probe (dynamic range of1.0-100% RH), located near the sample. The weight change, (massrelaxation) of the sample as a function of % RH was constantly monitoredby the microbalance (accuracy ±0.005 mg).

A sample (e.g., 20 mg) was placed in a tared mesh stainless steel basketunder ambient conditions. The sample was loaded and unloaded at 40% RHand 25° C. (typical room conditions). A moisture sorption isotherm wasperformed as outlined below (2 scans giving 1 complete cycle). Standardisotherms were performed at 25° C. at 10% RH intervals over a 0-90% RHrange. Data analysis was carried out using Microsoft Excel using DVSAnalysis Suite v6.2 (or 6.1 or 6.0).

In a cycle of 2 scans, the first scan was performed with adsorption of40-90% RH, followed by a second scan with desorption of 90-0% RH andadsorption of 0-40% RH, with intervals of 10% RH, at 25° C. withstability dm/dt of 0.002% ° C./min. The sorption time was 6 hr time out.

The sample was recovered after completion of the isotherm andre-analyzed by XRPD. Custom moisture sorption methods were alsoperformed at 25° C. at fixed % RH intervals over a 0-95% RH range, withthe purpose to fully understand the sorption/desorption behavior of thecompound under elevated conditions. The custom method performed for eachGVS experiment was provided in Tables 2-4 below.

TABLE 2 Custom GVS method at high % RH (HighRH, Steps 1 and 2) andSingle Cycle GVS method at high % RH (HighRH_Desorp_3, Steps 1, 2, 3,and 4) Steps Parameter 1 2 3 4 Adsorption/ 40-80 90, 95 90-0 0-40Desorption Intervals 10 — 10 10 (% RH) Sorption time 6 hr Held at each 6hr 6 hr time out RH for 800 mins time out time out Stability dm/dt 0.002— 0.002 0.002 (% ° C./min)

TABLE 3 Custom Double Cycle GVS method (HighRH_DoubleCycle_2) StepsParameter 1 2 3 4 5 6 Adsorption/Desorption 40-80 90 95 90-0 0 0-40Intervals (% RH) 10 — — 10 — 10 Sorption time 6 hr time Held at Held for6 hr time Held 6 hr time out each RH 1,600 out for 800 out for 800 minsmins mins Stability dm/dt 0.002 — — 0.002 — 0.002 (% ° C./min)

TABLE 4 Custom Double Cycle GVS method (P2803-J06994_3) Steps Parameter1 2 3 4 5 Adsorption/ 40-80 90-95 90-0 0 0-40 Desorption Intervals (%RH) 10 — 10 — 10 Sorption time 6 hr time Held at 6 hr time Held 6 hr outeach RH out for 800 time for 800 mins out mins Stability dm/dt 0.002 —0.002 — 0.002 (% ° C./min)

-   J. Ion Chromatography (IC)

Data were collected on a Metrohm 930 Compact IC Flex with 858Professional autosampler and 800 Dosino dosage unit monitor, using ICMagicNet software v3.1. Accurately weighed samples were prepared asstock solutions in an appropriate dissolving solution and dilutedappropriately prior to testing. Quantification was achieved bycomparison with standard solutions of known concentration of the ionbeing analyzed. IC method for anion chromatography was performed on aMetrosep A Supp 5-150 IC column (4.0×150 mm) at ambient temperature anda flow rate of 0.7 mL/min with injections of various μL. The eluent usedwas 3.2 mM sodium carbonate, 1.0 mM sodium hydrogen carbonate in a 5%acetone aqueous solution. A conductivity detector was used fordetection.

Example 1

Preparation and Characterization of Crystalline Forms 1, 2, and 3 ofRAD1901-2HCl

RAD1901 in EtOH was added to EtOAc and the resultant mixture was heateduntil dissolution. The solution was cooled to approximately 20° C. andtreated with 2.1 eq HCl in EtOH. The solution was concentrated and theresultant mixture was treated with EtOAc at approximately 20° C. andfiltered to yield RAD1901 as its bis-HCl salt, suitable for furtherprocessing according to the methods of form conversion provided in thisdisclosure.

Two samples of RAD1901-2HCl, Samples 1 and 2, were prepared. Sample 1was prepared by dissolving RAD1901-2HCl in a mixture of water andethanol (1.5:19). The water content was reduced to <0.5% by azeotropicdistillation and the concentrated solution was diluted with ethylacetate. The mixture was stirred at ambient temperature for at least 2hours and then the solid was collected by filtration. Sample 2 wasprepared by dissolving RAD1901-2HCl in methanol. Ethyl acetate was addedto the solution and the resulting mixture was stirred for at least 1hour at ambient temperature. The solid was collected by filtration.

Samples 1 and 2 were characterized by XRPD at various conditions. XRPDpatterns were collected for the samples at ambient condition as thesamples were provided; at variable temperature (VT-XRPD); at variablehumidity (VH-XRPD); after the samples were exposed to 40° C./75% RH for1 week and 25° C./97% RH for 1 week, respectively; and after a GVSmeasurement wherein the samples were exposed to 0-90% RH. Samples 1 and2 were also characterized by ¹H NMR, TGA, DSC, KF, IC, GVS (exposed to0-90% RH), PLM, SEM, and HPLC (Table 5).

Characterizations of Sample 1 (majorly Form 1) and Sample 2 (mixture ofForm 2 and Form 3) show that Form 1 was stable, had lower hygroscopicityand better thermal properties than Form 2. Additionally, Form 1 could beconverted to the hydrate Form 3 at high RH (>90%) (e.g., for 7 days);Form 3 of RAD1901-2HCl could also be prepared by exposing Form 2 to >40%RH for 7 days; Sample 2 (mixture of Form 2 and Form 3) could beconverted to Form 1 when heated at above 175° C. at <90% RH; and Form 2may also be prepared by exposing Form 3 to <40% RH for 8 hr. Thus,limiting the level of water/humidity in the preparation of RAD1901-2HClmay be beneficial to prepare Form 1 of RAD1901-2HCl. In certainembodiments, the percentage of water present in the preparation methodwas below 5% v/v and water content was determined by e.g. Karl Fischertitration (KF).

TABLE 5 Characterization of RAD1901-2HCl Samples 1 and 2 Character-ization Method Sample/Method Sample 1 Sample 2 HPLC N/A 99.2% AUC 99.2%AUC (FIG. (Purity %, (FIG. 2A) 3A) AUC) ¹H-NMR N/A Consistent withConsistent with structure structure (FIG. 3B) (FIG. 2B) XRPD Ambientcondition Crystalline, Crystalline, Form 1 (FIG. mixture 4B) of Form 2and 3 (FIG. 5A) XRPD Storage at 40° C./75% Form 1 (FIG. Form 3 (FIG. 5B)RH for 1 week 4B) XRPD Storage at 25° C./97% Form 3 Form 3 (FIGS. 5B RHfor 1 week (FIGS. 4B and 5C) and 5C) VT-XRPD N/A N/A Anhydrous Form 2obtained on heating to 100° C. Sample melted~160° C. and recrystallizedas Form 1 above 175° C. (FIG. 5D). VH-XRPD N/A Form 1 Conversion toconverted to Form 3 at > 90% Form 3 over 24 RH (FIG. 5E). hr at~95% RHForm 2 at 0% (FIG. 4C) RH (FIG. 5F) XRPD GVS (uptake 0-90% Form 1 (FIG.Mixture of form 2 post GVS RH) 4D) and 3 (FIG. 5G) XRPD GVS (HighRHmethod, FIG. 4E N/A post GVS HighRH_Desorp_3 method, Table 2) XRPD GVSFIG. 4F N/A post GVS (HighRH_Desorp_3's 1 cycle andHighRH_Double_Cycle's 2 cycles, Tables 3 and 4) XRPD 0% RH FIG. 4G FIG.5H (Form 2), (Form 1), FIG. 4H FIG. 4H XRPD 92% RH — FIG. 5I (Form 3),FIG. 4H GVS Uptake 0-90% RH 1.8% wt. 6.7% wt. (reversible) from 0-40%(FIGS. 6A RH; 2.0% wt. from and 6B) 40-90% RH (FIGS. 7A and 7B) GVSHighRH method, FIGS. 6C and N/A Table 2 6D GVS HighRH_Desorp_3 FIGS. 6Eand N/A method, Table 2 6F GVS HighRH_DoubleCycle_2 FIGS. 6G and N/Amethod, Tables 3 and 4 6H TGA N/A 0.4% weight 6.1% weight loss lossbetween between ambient and ambient and 100 ° C. (FIG. 200° C. (FIG. 9,8

 , top) top) DSC N/A Endotherm at Endotherm at 218° C. (onset) 157° C.150.0 J/g (melt) (onset) 87 J/g (FIG. 8, (melt), exotherm at bottom)187° C. (recryst.), endotherm at 207° C. (onset) 33 J/g (melt as Form 1)(FIG. 9, bottom) KF N/A 0.7% water 3.9% water (conducted at (conducted200° C.) at 200° C.) IC N/A 2.0 eq (adjusted 1.9 eq (adjusted for TGAmass for TGA loss) mass loss) PLM N/A Crystalline Crystalline platesplates (FIG. (FIG. 11) 10A) SEM N/A Stacked plates Stacked plates with(FIGS. 12A- cracks (evidence 12C) of desolvation) (FIGS. 13A-13C)

RP-HPLC analysis of Samples 1 and 2 showed 99.2% AUC collected at 255 nm(FIG. 2A for Sample 1, and FIG. 3A for Sample 2). ¹H-NMR of Samples 1and 2 collected in d₆-DMSO are consistent with RAD1901-2HCl structure(FIG. 2B for Sample 1, and FIG. 3B for Sample 2).

Sample 1 was majorly Form 1 of RAD1901-2HCl having XRPD Pattern 1, FIG.4G at 0% RH, with peaks summarized in Table 7. Sample 1 showed XRPDpattern slightly different at ambient RH (FIG. 4A, Table 6). Sample 2was a mixture of Forms 2 and 3 of RAD1901-2HCl. Form 2 showed XRPDPattern 2 (FIG. 5H, sample 2 at 0% RH, peaks summarized in Table 8) andForm 3 showed XRPD Pattern 3 (FIG. 5I, sample 2 at 92% RH, peakssummarized in Table 9).

TABLE 6 XRPD peaks of Sample 1 at ambient RH (Pattern 1) Angle degrees,Intensity Caption (2θ) (%)  7.1° 7.1 93.1  7.8° 7.8 6.9  8.1° 8.1 4.1 8.6° 8.6 7.2  9.1° 9.1 5.6 11.0° 11.0 20.8 11.1° 11.1 9.2 11.4° 11.49.1 12.0° 12.0 30.3 12.1° 12.1 16.5 12.7° 12.7 5.9 13.8° 13.8 39.6 14.2°14.2 100.0 14.8° 14.8 4.3 15.6° 15.6 3.7 16.1° 16.1 24.3 17.3° 17.3 5.217.8° 17.8 12.7 18.4° 18.4 58.5 18.9° 18.9 29.9 19.7° 19.7 16.5 20.2°20.2 12.9 21.1° 21.1 10.3 22.1° 22.1 13.3 23.0° 23.0 21.9 23.2° 23.213.7 23.6° 23.6 16.1 24.0° 24.0 18.0 24.6° 24.6 10.4 25.1° 25.1 43.925.7° 25.7 6.7 26.5° 26.5 23.3 27.1° 27.1 30.4 27.3° 27.3 12.8 27.8°27.8 10.4 28.4° 28.4 14.6 28.7° 28.7 9.6 29.1° 29.1 14.9 29.9° 29.9 24.630.3° 30.3 15.3 30.5° 30.5 10.3

TABLE 7 XRPD peaks of Sample 1 at 0% RH (Pattern 1) Angle degrees,Intensity Caption (2θ) (%)  7.1° 7.1 100.0  7.7° 7.7 7.9  8.6° 8.6 12.0 9.1° 9.1 10.0 11.0° 11.0 40.9 11.2° 11.2 17.9 11.4° 11.4 18.0 12.0°12.0 62.0 12.7° 12.7 6.7 13.8° 13.8 67.5 14.3° 14.3 86.4 14.8° 14.8 4.115.5° 15.5 4.8 16.2° 16.2 36.3 16.8° 16.8 7.8 17.3° 17.3 7.9 17.8° 17.820.1 18.3° 18.3 83.5 18.9° 18.9 47.3 19.7° 19.7 20.5 20.2° 20.2 19.820.9° 20.9 7.6 21.2° 21.2 13.6 22.0° 22.0 24.7 23.1° 23.1 30.7 23.6°23.6 25.3 24.0° 24.0 27.5 24.5° 24.6 15.3 25.1° 25.1 58.4 25.8° 25.8 9.826.5° 26.5 31.1 27.2° 27.2 43.4 27.5° 27.5 12.3 27.8° 27.8 12.7 28.5°28.5 17.6 28.7° 28.7 11.6 29.1° 29.1 21.1 30.0° 30.0 25.8 30.3° 30.323.8 30.5° 30.5 16.1

TABLE 8 XRPD peaks of Sample 2 at 0% RH (Pattern 2) Angle degrees,Intensity Caption (2θ) (%)  6.3° 6.3 100.0  8.2° 8.3 6.0  9.8° 9.8 19.111.5° 11.5 11.5 12.1° 12.1 6.1 12.5° 12.5 32.9 13.4° 13.4 21.7 13.8°13.8 3.8 14.6° 14.6 2.1 15.4° 15.4 23.5 15.8° 15.8 14.2 17.4° 17.4 13.917.8° 17.8 8.0 18.3° 18.3 23.3 18.8° 18.8 13.3 19.9° 19.9 16.1 20.3°20.3 7.4 21.1° 21.1 13.2 21.5° 21.5 6.3 21.9° 21.9 15.8 22.5° 22.5 14.623.0° 23.0 15.1 23.9° 23.9 7.0 24.7° 24.7 10.9 25.0° 25.0 18.2 25.5°25.5 6.7 26.2° 26.2 9.9 27.0° 27.0 6.2 28.0° 28.0 18.3 29.3° 29.3 4.829.9° 29.9 20.4 30.3° 30.3 6.4

TABLE 9 XRPD Peak of Sample 2 at 92% RH (Pattern 3) Angle degrees,Intensity Caption (2θ) (%)  5.8° 5.8 100  8.1° 8.1 10  9.5° 9.5 35.211.5° 11.5 33.6 12.4° 12.4 29.5 12.6° 12.7 22 13.1° 13.1 34.5 13.6° 13.613.1 15.1° 15.1 34.8 16.1° 16.1 16.4 16.9° 16.9 6.7 17.4° 17.4 19 18.0°18.0 17.5 18.4° 18.4 9.7 18.9° 18.9 19.1 19.9° 19.9 11.4 21.3° 21.3 50.121.7° 21.7 27.5 22.4° 22.4 19.3 22.8° 22.8 29.9 23.3° 23.3 40 24.2° 24.222.2 24.8° 24.8 41.8 25.4° 25.4 18 26.2° 26.2 19.5 27.4° 27.4 26.9 27.6°27.6 23.3 28.9° 28.9 11.1 29.3° 29.3 10.2 30.5° 30.5 14.3

Form 1 was stable after storage at 40° C./75% RH for 1 week and afterexposure to 0-90% RH in a GVS, as confirmed by unchanged XRPD pattern(Pattern 1) of Form 1 sample pre- and post-GVS. However, Form 1 wasconverted to Form 3 after storage at 25° C./97% RH for 1 week.

Form 1 was relatively non-hygroscopic between 0 and 90% RH as shown inGVS data (FIGS. 6A-6B). No changes were observed in the XRPD patternpre- and post-GVS analysis (FIG. 4D).

Form 1 was stable to storage at 40° C./75% RH for 7 days (from XRPDanalysis), but storage at 25° C./97% RH for 7 days resulted inconversion towards a hydrated state Form 3 (see FIG. 4B).

An overlay of the new patterns obtained upon storage of Sample 1 andSample 2 at elevated conditions is provided in FIG. 5C, which aresubstantially consistent with Form 3. Importantly, this indicates thatupon prolonged exposure to high RH, Sample 1 (Form 1) was converted tothe hydrate Form 3.

To further explore the humidity behavior of Sample 1 (Form 1) uponexposure to high RH (>90%), custom GVS experiments were designed andcarried out. Initially, the sample was treated by holding at 90 and then95% RH for ˜12 hours to see if hydrate formation could be observed(HighRH method of Steps 1 and 2 of Table 2, FIGS. 6C-6D).

FIGS. 6C-6D (HighRH method of Steps 1 and 2 of Table 2) shows Sample 1(Form 1) took up 5-6% wt. when held at 95% RH for ˜12 hours, indicatinghydrate formation. XRPD analysis of the sample post-GVS experiment(HighRH, red in FIG. 4E) showed significant changes compared to that ofForm 1 (black in FIG. 4E), with similarities to both the hydrated stateForm 3 and the anhydrous Form 1. FIG. 4E suggested a mixture of statesor incomplete conversion from Sample 1 to the hydrate form.

To test the stability of the hydrated state, GVS method HighRH_Desorp_3was designed with a desorption step and subsequent adsorption (see Table2 with steps 1-4, FIGS. 6E-6F).

The GVS data in FIGS. 6E-6F shows that the hydrated state (at 95% RH)was stable to desorption until near 0% RH, and upon adsorption from 0 to40% RH, the sample did not convert back to anhydrous Form 1, but insteadirreversibly converted to a new state (indicating a mixture of hydrateand anhydrous). Furthermore, the shape of the adsorption step from 0 to40% was observed to be highly similar to that of Form 2 (see FIG. 7A).XRPD analysis of the sample post-GVS experiment (‘HighRH_Desorp 3’)confirmed that a mixture of Form 1 and Form 3 was present (see FIG. 4E),as shown by starred peaks (indicating peaks present in either the XRPDpattern of the anhydrous or hydrated form). The XRPD patterns obtainedfor Sample 1 post GVS of HighRH_Desorp_3 is shown in green.

Finally, to ensure complete conversion to the anhydrous and hydratedforms, a GVS experiment was designed to increase both the length of thedesorption step at 0% RH, and the adsorption step at 95% RH,respectively (Table 3). Based on the weight stabilization observed inthe kinetic plots for Sample 1 in HighRH and HighRH_Desorp_3 methodsdiscussed above (FIGS. 6D and 6F), a holding time of 800 mins at 0% RHand 1600 mins at 95% RH were chosen. A double cycle was also recordedfor this experiment to observe whether the sample would return to Form 1or form a mixed anhydrous/hydrated species (see Table 3, FIGS. 6G-6H).

The GVS data (FIGS. 6G-6H) show that after complete desorption at 0% RH,and subsequent re-adsorption, the sample continued to uptake water andformed a mixed anhydrous/hydrated species. This species converted to thehydrate at 90-95% RH (Form 3), which remained stable during desorptionuntil 40%, below which the sample desorbed sharply. Subsequentadsorption from 0 to 40% RH followed this step-wise transition, whichcan be clearly observed in the GVS Isotherm Plot of Sample 2 (see FIG.7A). This GVS data provides clear evidence that the Sample 1/Form 1material irreversibly converted to a hydrate (Form 3) under exposure tohigh RH (>90%), and upon desorption shifts into an equilibrium betweenthe anhydrous state (Form 2) and the hydrated state (Form 3). XRPDanalysis of the sample post-GVS experiment ('HighRH_DoubleCycle_2′)confirmed the formation of the hydrate (Form 3), see FIG. 4F.

To fully characterize the polymorphic behavior of Samples 1 and 2 atvariable humidity, and to collect reference XRPD patterns for the ‘pure’anhydrous Form 1 and Form 2 material, and ‘pure’ hydrated Form 3material, Variable Humidity (VH) XRPD experiments were conducted onSamples 1 and 2. Initially, VH-XRPD experiments were conducted usingSample 1, and XRPD diffractograms were collected at selected humidityvalues, in line with those collected during GVS experiments (see FIGS.6E-6F). XRPD diffractograms were collected initially at ambient RH, thencollected over 24 hours at ˜95% RH and finally collected duringdesorption steps to 0% RH and over 10 hours at 0% RH (see FIG. 4C). Fullmethod details are provided in Table 10 below.

TABLE 10 Experimental conditions for collection of VH experiment onSample 1 (sample: J106994_D8_VH, method: P2803-06NOV15) Desired RecordedMeasured delay Scan time Humidity humidity (hold) time (hrs) (hrs)Ambient 53.7 0  0.69* 94 96.1 2 0.69 94 95.3 2 0.69 94 94.9 2 0.69 9494.7 2 0.69 94 94.5 2 0.69 94 94.5 2 0.69 94 94.4 2 0.69 94 94.3 2 0.6994 94.3 2 0.69 94 94.2 2 0.69 80 82.4 1 0.69 70 72.8 1 0.69 60 63.6 10.69 50 51.7 1 0.69 40 40.3 1 0.69 30 29.3 1 0.69 20 17.3 1 0.69 10 5.91 0.69 0 0 1 0.69 0 0 4 0.69 0 0 4 0.69 10 5.8 2 0.69 20 17.2 2 0.69 3029.1 2 0.69 40 40.0 2 0.69 *each scan was 41 m 28 s (0.69 hrs)

The VH-XRPD experiment was unable to show a direct conversion from thestarting material Sample 1 (Form 1) to the hydrated state (Form 3) over24 hours at ˜95% RH (see FIG. 4C). However, there were subtle changes inthe diffractogram pattern observed at ˜95% RH, compared to that of thestarting material at ambient RH and at 0% RH (see starred peaks). Thesechanges included a shoulder at 12 degrees 2θ and an additional peak at19 degrees 2θ and indicated a slow conversion towards the hydrated state(see post 25/97′ in FIG. 4C). Thus, Form 1 may have converted to Form 3(hydrate) over time, as supported by GVS data (FIGS. 6E-6F). Onepossible explanation for the slower kinetics in VH-XRPD is that VH-XRPDexperiments relied on changes in the crystal structure of a sample at anexposed surface layer to varying humidity, whereas GVS experimentsallowed all surfaces of the sample to be exposed as the sample wassuspended in a wire basket.

Thermal analysis of the supplied materials showed that Sample 1 wasanhydrous (by TGA and KF), and had no thermal events prior to melt ordegradation. In comparison, Sample 2 had a complex thermal profile byDSC (see FIG. 9B) and was found to be a hydrate (by TGA and KF). The DSCtrace showed that Sample 2 desolvated upon heating from ambient to 150°C., melted at ˜157° C. and recrystallized at ˜187° C. (see FIG. 9B). TGAdata showed that this desolvation event corresponded to a loss of 6.2%weight, equivalent to 2 molecules of water.

Variable Temperature XRPD (VT-XRPD) experiments were therefore conductedto examine the thermal behavior of Sample 2 observed by DSC (see FIG.9B). VT-XRPD analysis shows that Sample 2 converted to the anhydrousstate (Form 2, red) upon heating above 100° C., then melted andrecrystallized at ˜175° C. (blue) as Form 1 material (FIG. 5D).

This indicates that Sample 2 as a mixture of Forms 2 and 3 can beconverted to Form 1 by recrystallization above 175° C. However, it isclear that Form 1 material irreversibly converted to the hydrate Form 3under exposure to high RH (>90%).

VH-XRPD experiments were also conducted using Sample 2 and XRPDdiffractograms were collected at selected humidity values of 0% RH(Table 12) and 90% RH (Table 11, to obtain reference XRPD patterns forthe ‘pure’ anhydrous Form 2 and ‘pure’ hydrated Form 3 respectively. TheGVS Kinetic Plot collected for Sample 2 (see FIG. 7B) indicatedrelatively fast kinetics for conversion from anhydrous to hydrated form,therefore XRPD patterns were collected at time points of up to 10-14hours (see FIGS. 5E-5F).

TABLE 11 Experimental conditions for collection of VH experiment onSample 2 at high RH (sample: J06993_D8_VH_90, method: P2803-11NOV15)Desired Recorded Measured delay Scan time Humidity humidity (hold) time(hrs) (hrs) 40 41.8 0 0.69 90 93.4 2 0.69 90 92.1 2 0.69 90 91.6 2 0.6990 91.6 2 0.69

TABLE 12 Experimental conditions for collection of VH experiment onSample 2 at 0% RH (sample: J06993_D8_VH_0, method: P2803-12NOV15)Desired Recorded Measured delay Scan time Humidity humidity (hold) time(hrs) (hrs) 0 0 2 0.69 0 0 2 0.69 0 0 2 0.69 0 0 2 0.69 0 0 0.69 0.69

As shown in FIG. 5E, slight changes in the XRPD pattern of Sample 2 wereobserved between ambient (42% RH) and 92-93% RH (see starred peaks),showing conversion toward the hydrated state (as represented by the XRPDpattern post storage at 25° C./97% RH). However, the kinetics remainedrelatively slow. Based on these observations, the XRPD pattern foranhydrous Sample 2 (at 0% RH) was collected after drying a sample in avacuum oven (RT, 8 hours) (see FIG. 5F). The XRPD pattern collected at0% RH was consistent with a sample of anhydrous Sample 2 produced byheating to 100° C. on a VT-XRPD stage (see experimental section aboveand FIG. 5D), and therefore provided a reference for the anhydrous Form2.

Form 3 in Sample 2 was converted to Form 2 when Sample 2 was heated to100° C. Sample 2 started to melt around 160° C. and recrystallized asForm 1 at above 175° C. The characterization data of Samples 1 and 2 aresummarized in Table 5.

GVS experiments showed that Sample 2 was hygroscopic with a mass uptakeof 6.7% wt. from 0% to 40% RH, plateauing above 40% RH (2.0% wt. from40-90% RH) (see FIGS. 7A-7B). Thus, an equilibrium existed between theanhydrous and hydrated states for Sample 2 at near ambient RH (e.g.,40-65% RH).

The XRPD pattern collected for Sample 2 varied depending on theprevailing RH during measurement. For XRPD diffractograms pre- andpost-GVS, see FIG. 5G, which showed that a mixture of Form 2 and Form 3existed in between 0% and 90% RH (post GVS).

Example 2

Solubility Assessment of Polymorphic Forms of RAD1901-2HCl

Solubility assessment was carried out on the Sample 1 of RAD1901-2HCl(majorly Form 1 shown by XRPD) in 24 solvent systems in HPLC vials(sample IDs: A1 to A24). RAD1901-2HCl (25 mg) was treated withincreasing volumes of solvent until the material fully dissolved oruntil a maximum of 60 vol had been used (Table 13).

TABLE 13 Solubility assessment and polymorph screen on Form 1 ofRAD1901-2HCl Cooled After Sample 10 20 40 60 to 5 50/RT FIG. ID Solventvol. vol. vol. vol. ° C. maturation Evaporation XRPD No. A1 n-Heptane XX X X N/A X N/A Form 1 14A A2 Propyl acetate X X X X N/A X N/A Form 114A A3 Ethyl acetate X X X X N/A X N/A Form 1 14A A4 Isopropyl X X X XN/A X N/A Form 1 14A acetate A5 MIBK X X X X N/A X N/A Form 1 14A A62-propanol X X X X N/A X N/A Form 3* 14C A7 MEK X X X X N/A X N/A Form1* 14A A8 1-propanol X X X X N/A X N/A Form 1 14A A9 Acetone X X X X N/AX N/A Form 3* 14C A10 Ethanol X X X X N/A X N/A Form 1 14A A11 DimethylS S N/A S S — sulfoxide A12 Water +/− S S N/A Solid Form 3 14C A13 TBMEX X X X N/A X N/A Form 1 14B A14 1,4-Dioxane X X X X N/A X N/A Form 114B A15 Toluene X X X X N/A X N/A Form 1 14B A16 1,2- X X X X N/A X N/AForm 1 14B dimethoxyethane A17 Tetrahydrofuran X X X X N/A X N/A Form 114B (THF) A18 Dichloromethane X X X X N/A X N/A Form 1 14B A19Acetonitrile X X X X N/A X N/A Form 1 14B (ACN) A20 Methanol +/− SPlatelet N/A N/A Form 3 14C crystal A21 Nitromethane X X X X N/A SSolids Form 1 14B A22 10% +/− S Some N/A N/A Form 3* 14C water/EtOHcrystal A23 10% X X +/− S S N/A Solids, Form 3 14C water/IPA greensolution A24 10% X X +/− S S N/A Solids Form 3 14C water/THF Legend: X =suspension; S = solution; +/− = nearly dissolved; * = poorlycrystalline; N/A = not applicable

After each addition of solvent, the system was stirred for 5 to 10minutes at 25° C., then shaken at 50° C. for 5 to 10 minutes, andobservations made. Samples were allowed to stand at room temperature for5 min before the addition of a new aliquot of solvent. After theassessment was completed, the suspensions obtained were matured(maturation) and the clear solutions were cooled (cooling) and slowlyevaporated (evaporation) as described below. All solids recovered frommaturation, cooling and evaporation experiments were analyzed by highresolution XRPD.

The suspensions obtained during the solubility assessment were maturedby shaken in a maturation chamber between 50° C. and RT (8 hr per cycle)for up to 5 days. Then the mixture was allowed to stand at roomtemperature for 10 minutes. The resulting solids were filtered and airdried and analyzed by XRPD. The clear solutions obtained duringmaturation were evaporated in ambient conditions and the resultingresidues were analyzed by XRPD.

The clear solutions obtained during the course of the solubilityassessment were cooled on a Polar Bear device from 50° C. to 5° C. at0.1° C./min. Solids obtained upon cooling were recovered from the vials,air dried and analyzed by XRPD. If no solid was obtained, the solutionswere evaporated slowly through a needle inserted into the septum cap ofthe vial until a solid appeared at ambient conditions and the resultingsolids were filtered, air dried and analyzed by XRPD.

The solubility assessment of the Sample 1 in different solvent systemsshowed that the compound had low solubility in alcohols, esters, andhydrocarbon solvents, but was highly soluble in water. XRPD analysis ofsolids recovered after maturation, cooling and evaporation (in thesolvents listed in Table 13) found that either anhydrous Form 1 orhydrated Form 3 were produced (FIGS. 14A-14C). Consistent with thesolid-state characterization of Sample 1 in Example 1, slurrying inwater or water/solvent systems produced the hydrated state, Form 3.Pattern 3 was also observed from slurrying in 2-propanol, acetone andmethanol, but it is likely that the hydrate resulted from residual waterpresent in the solvent stock solutions (anhydrous solvents were not usedin this screen).

During these screening experiments, it was observed that one sample(A20) produced crystals of plate morphology (see FIG. 10B), and wassubmitted for Single Crystal analysis. However, these crystals werefound to exist as stacks (as seen by SEM, see FIGS. 12A-12C), not singlecrystals and were therefore unsuitable for collection by SCXRD. Analysisof the crystals by XRPD found that the material was consistent with ahydrated state, and most closely resembled Pattern 3 (FIG. 14C).

Example 3

Preparation and Characterization of Amorphous RAD1901-2HCl

-   A) Preparation and characterization of amorphous RAD1901-2HCl

As Sample 1 of RAD1901-2HCl showed high solubility in water andt-butanol/water (1:1), amorphous RAD1901-2HCl was prepared from each ofthese solvents by lyophilization. RAD1901-2HCl (100 mg) was placed intoa scintillation vial and appropriate solvent systems tested fordissolution of the material. Water or t-butanol/water (1:1) (20-30 vol.,2-3 mL) was added to the sample at RT, and the mixture was vortexeduntil dissolution, and filtered to remove any remaining solid particles.The solution was frozen in a dry ice/acetone bath and the solventremoved by lyophilization. The resulting solids were analyzed foramorphous content by XRPD (FIG. 15A), counterion identity by IC, purityby HPLC and NMR, and thermal properties by TGA and DSC (Table 14).

TABLE 14 Characterization data for amorphous RAD1901-2HCl produced bylyophilisation Technique/ Lyophilization in t- Sample ID Lyophilizationin water Butanol/Water(1:1) XRPD Amorphous (FIG. 15A) Amorphous (FIG.15A) ¹H-NMR Consistent with starting Consistent with starting material(FIG. 16) material, 0.3 eq. residual t- butanol (FIG. 16) HPLC (Purity%) 99.3% AUC 99.2% AUC DSC Broad endotherm from Broad endotherm 25° C.to 140° C., from 25° C. to endotherm at 149° C. 140° C., endotherms at(onset) (FIG. 17A) 103° C. (onset) and 147° C. (onset) (FIG. 17A) TGA6.5% wt. loss from Two steps: 5.3% wt. loss RT to 190° C. from RT to120° C. and (FIG. 17B) 1.8% wt. loss from 120° C. to 190° C. (FIG. 17B)IC Average = 1.79 Average = 1.79 (adjusted (adjusted for for TGA wt.loss = 1.92) TGA wt. loss = 1.93) mDSC Broad endotherm Broad endotherm0-100° C. 0-150° C. masks masks any Tg any Tg (FIG. 17C) XRPD poststorage Consistent with Form 3 Consistent with Form 3 at 25° C./97%(FIG. 15B) (FIG. 15B) RH (10 days) XRPD post storage Consistent withForm Consistent with Form 3 at 40° C./75% 3 (FIG. 15C) (FIG. 15C) RH (10days)

-   B) Scale-up Preparation of Amorphous RAD1901-2HCl

In a scale-up preparation of amorphous RAD1901-2HCl, RAD1901-2HCl (600mg) was dissolved in water (20 vol., 12 mL) and filtered to remove anyremaining solid particles. The solution was then aliquoted into 24 HPLCvials, frozen in a dry ice/acetone bath and the solvent removed bylyophilisation. Solids produced by lyophilization were used directly insolubility assessment and polymorph screens in Example 4.

Example 4

Solubility Assessment and Polymorph Screen of Amorphous RAD1901-2HCl

-   A) Solubility assessment and polymorph screen of amorphous    RAD1901-2HCl

Amorphous RAD1901-2HCl prepared as described in Example 3B was useddirectly in solubility assessment and polymorph screens (Table 15). XRPDpatterns were further obtained for amorphous RAD1901-2HCl prepared usingother solvents.

TABLE 15 Solubility assessment and polymorph screen on amorphousRAD1901-2HC1 After PLM after XRPD After XRPD Sample 10 maturationmaturation post maturation post FIG. ID Solvent vol. at 25° C. at 25° C.25° C. at 50° C. 50° C./RT No. B1. n-Heptane X X No visible N/A XAmorphous 18D crystalsX B2. Propyl X X No visible N/A X Form 2/3 18Bacetate crystalsX B3. Ethyl acetate X X No visible N/A X Form 2/3 18BcrystalsX B4. Isopropyl X X No visible N/A X Form 2/3 18B acetatecrystalsX B5. MIBK X X No visible N/A X Form 3 18B crystalsX B6.2-propanol X X No visible N/A X Form 1⁺ 18D crystalsX B7. MEK X X Novisible N/A X Form 1⁺ 18D crystalsX B8. 1-propanol X X No visible N/ACrystalline Form 1 18A crystalsX material B9. Acetone X X No visible N/AX Form 1* 18D crystalsX B10. Ethanol X X No visible N/A Fine Form 1 18AcrystalsX crystals B11. Dimethyl S S S N/A S S — sulfoxide B12. Water SX Fine Form 3 Lath Form 3 18C needles crystals B13. TBME X XBirefringent Amorphous Some Poor 18D solid crystals crystalline B14.1,4-Dioxane X X No visible N/A X Poor 18D crystalsX crystalline B15.Toluene X X No visible N/A Fine Form 3 18B crystalsX crystals B16. 1,2-X X No visible N/A Crystalline Form 3* 18C dimethoxyethane crystalsXmaterial B17. Tetrahydrofuran X X No visible N/A Fine Form 1* 18AcrystalsX crystals (THF) B18. Dichloromethane X X No visible N/ACrystalline Form 3 18B crystalsX material B19. Methanol X Crystal CubicForm 3 Green N/A 18C crystals solution B20. Acetonitrile X X No visibleN/A Crystalline Form 1 18A crystalsX material B21. Nitromethane X XCubic/needle Form 1 Needle Form 1 18A crystals crystals B22. 10% S SNeedle/Lath Form 3 Green N/A 18C water/EtOH crystals solution B23. 10% XX Fine Form 3 Fine Form 3 18C water/IPA crystals crystals B24. 10% X XFine Form 3 Fine Form 3 18C water/THF crystals crystals Legend: X =suspension; S = solution; +/− = nearly dissolved; * = poorlycrystalline; N/A = not applicable; ⁺Possibly some Form 3 present

In the polymorph screen of the amorphous RAD1901-2HCl prepared asdescribed in Example 3B, an aliquot of each sample was examined for itsmorphology under the microscope, both after maturing at 25° C., andafter maturing at 50° C./RT. If any crystalline material was observed ateither maturation stage, the resulting solids were filtered, air driedand analyzed by high resolution XRPD. XRPD analysis of samples from thepolymorph screen showed that only three distinct patterns could beobserved: patterns for Forms 1, 2 and 3 previously observed (FIGS.18A-18D). In some instances, the sample appeared to be a mixture ofvarious polymorphic forms, e.g. Form 2 and Form 3 (FIGS. 18B-18C),similar to the mixture of Forms 2 and 3 in Sample 2 having anequilibrium between the two solid forms, depending on the prevailing RH.

Similarly, samples prepared from 2-propanol and MEK may contain a mix ofanhydrous Form 1 and hydrated Form 3 material (FIG. 18D).

PLM images were obtained for crystals obtained during polymorph screensusing amorphous RAD1901-2HCl prepared as described in Example 3B viacooling in methanol (FIG. 19A), maturation in water (FIG. 19B), ormaturation in nitromethane (FIG. 19C), respectively (FIG. 19).

Despite collecting high resolution XRPD data, some samples were alsopoorly crystalline and their pattern could not be definitively assigned,but closely resembles that of Form 1 (FIG. 18D). Therefore, noadditional new patterns have been observed in these screens usingamorphous RAD1901-2HCl.

-   B) Solubility Assessment of Amorphous RAD1901-2HCl in Water/Organic    Solvent System

Samples of amorphous RAD1901-2HCl were prepared in water/organic solventmixtures containing varying ratios of water. The organic solvents chosenwere anhydrous ethanol, methanol and ethyl acetate. The percentage ofwater in the water/organic solvent mixtures was varied between 0 and 10%(v/v) in order to place a limit on the level of water that can bepresent during production processes, and to retain formation of Form 1.Above this water activity limit, the hydrated Form 3 will be obtained,as shown by GVS experiments (see FIGS. 6G and 20A). It should be notedthat samples prepared in ethyl acetate, were either slurried inanhydrous ethyl acetate, or in water saturated ethyl acetate.

The results from the water/organic solvent experiment are given in Table16 and in FIGS. 20A-20C. The water activity values for eachwater/organic solvent mixture are provided in Table 16, and werecalculated using the reference given in Bell, Halling, Enzyme Microbiol.Technol. 1997, 20, 471, incorporated herein by reference.

TABLE 16 Solubility assessment and polymorph screen on amorphousRAD1901-2HC1 After stirring at 25° C. Sample Water 10 20 30 for 72 FIG.ID Solvent activity vol. vol vol hours XRPD No. C1. EtOH/H₂O 0.58 S XForm 3 20A (90:10) C2. EtOH/H₂O 0.39 X X Form 1 20A (95:5) C3. EtOH/H₂O0.20 X X Form 1 20A (98:2) C4. EtOH/H₂O 0.11 X X Form 1 20A (99:1) C5.MeOH/H₂O 0.33 S S S (90:10) C6. MeOH/H₂O 0.19 S Crystals Form 3* 20B(95:5) C7. MeOH/H₂O 0.08 +/− Crystals Form 2 20B (98:2) C8. MeOH/H₂O0.04 +/− Crystals Form 2 20B (99:1) C9. Ethyl acetate 0.00 X X X X Form1* 20C (anhydrous) C10. Water-saturated 0.77 X X X X Form 3 20C ethylacetate Legend: X = suspension; S = solution; +/− = nearly dissolved; *= poorly crystalline.

The water/organic solvent experiments demonstrate a water activity limitabove which the hydrated Form 3 was produced. Samples of amorphousRAD1901-2HCl obtained from Example 3b prepared in anhydrous ethanolcrystallized as Form 1 material, consistent with the XRPD patternobtained during polymorph screening of amorphous Sample 1 (see Table15). It is also known that ethanol solvent is used in the production ofForm 1 material of RAD1901-2HCl (Sample 1) during drug purificationprocesses (along with ethyl acetate). Crystals produced fromwater/ethanol were Form 1 up to a ratio of 5% water/ethanol, above whichthe hydrate Form 3 resulted. This equates to a water activity limit of0.39 (see Table 16), and indicates that at least on small-scale, up to5% water can be present during drug production process to produce Form1.

Amorphous RAD1901-2HCl in anhydrous methanol crystallized as Form 2having XRPD Pattern 2. This is consistent with the supplied batch ofsample 2, which was known to form during isolation of RAD1901-2HCl usingmethanol (and ethyl acetate) solvent. Crystals produced fromwater/methanol were Form 2 (anhydrous) up to a ratio of 2%water/methanol, above which the hydrate Form 3 having XRPD Pattern 3 wasproduced. This equates to a water activity limit of 0.08 (see Table 16),which is low, and may reflect the observations (by GVS, see FIG. 7A)that at relatively low (ambient) RH, Form 2 material converts to thehydrate Form 3 or a mixture of Forms 2 and 3.

Slurrying of amorphous RAD1901-2HCl in anhydrous ethyl acetate producedcrystals of Form 1 material, which supports the observation that Form 1could be isolated using ethanol and ethyl acetate solvents in drugproduction processes, whereas Form 2 could be produced using methanoland ethyl acetate. The ratio of water/ethyl acetate was not varied,since the water-saturated ethyl acetate has above 2.7% (v/v) water(e.g., 3.3% water at 20° C.), which equates to water activity of 0.77.Slurrying in water-saturated ethyl acetate produced the hydrate Form 3.

Example 5

A crystalline form of RAD1901-2HCl.

Example 6

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising a peak, in terms of 2-theta, at 7.1 degrees 2θ±0.2 degree 2θat about relative humidity 0%.

Example 7

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising a peak, in terms of 2-theta, at 7.1 degrees 2θ±0.2 degree 2θand/or 14.3 degrees 2θ±0.2 degree 2θ at about relative humidity 0%.

Example 8

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least two peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ and 18.3 degrees 2θ±0.2 degree 2θ at about relative humidity0%.

Example 9

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least three peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θand 12.0 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.

Example 10

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least four peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ and 18.9degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.

Example 11

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least five peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ and 11.0 degrees2θ±0.2 degree 2θ, at about relative humidity 0%.

Example 12

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least five peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relativehumidity 0%.

Example 13

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least seven peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relativehumidity 0%.

Example 14

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least eight peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relativehumidity 0%.

Example 15

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least nine peaks, in terms of 2-theta, selected from thegroup consisting of 7.1 degrees 2θ±0.2 degree 2θ, 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relativehumidity 0%.

Example 16

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising the peaks, in terms of 2-theta, of 7.1 degrees 2θ±0.2 degree2θ, 14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree2θ, at about relative humidity 0%.

Example 17

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patternsubstantially as shown in FIG. 4G at about relative humidity 0%.

Example 18

A solid form of RAD1901-2HCl, having a differential scanning calorimetry(DSC) thermogram comprising a melting onset at 218.2° C. and anendothermic peak at 232.1° C.

Example 19

The solid form of Example 18, having a differential scanning calorimetry(DSC) thermogram substantially as shown in the bottom figure of FIG. 8.

Example 20

A solid form of RAD1901-2HCl, having a thermogravimetric analysis (TGA)substantially as shown in the top graph of FIG. 8.

Example 21

A composition comprising RAD1901 wherein at least 5% w/w of the totalamount of RAD1901 is a solid form of any one of previous examples.

Example 22

A composition comprising RAD1901 wherein at least 25% w/w of the totalamount of RAD1901 is a solid form of any one of previous examples.

Example 23

A composition comprising RAD1901 wherein at least 50% w/w of the totalamount of RAD1901 is a solid form of any one of previous examples.

Example 24

A composition comprising RAD1901 wherein at least 90% w/w of the totalamount of RAD1901 is a solid form of any one of previous examples.

Example 25

A composition comprising RAD1901 wherein at least 95% w/w of the totalamount of RAD1901 is a solid form of any one of previous examples.

Example 26

A composition comprising RAD1901 wherein at least 98% w/w of the totalamount of RAD1901 is a solid form of any one of previous examples.

Example 27

A pharmaceutical composition comprising the solid form of any ofExamples 5-26 and one or more pharmaceutically acceptable excipients.

Example 28

A process for preparing a solid form of any of Examples 5-27 comprisingprecipitating from a solution comprising RAD1901-2HCl and a solvent, orslurrying RAD1901-2HCl in a solvent, wherein the solvent comprises anorganic solvent substantially free of methanol, and the content of wateris at or below 5% v/v.

Example 29

The process according to Example 28 wherein the solvent is selected fromthe group consisting of n-heptane, propyl acetate, ethyl acetate,isopropyl acetate, methyl isobutyl ketone (MIBK), methyl ethyl ketone(MEK), 1-propanol, ethanol, t-butyl methyl ether (TBME), 1,4-dioxane,toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane,acetonitrile, nitromethane, and mixtures thereof.

Example 30

A method of treating breast cancer comprising an administration to asubject in need thereof a solid form of any of Examples 5-26.

Example 31

The method of Example 30 wherein said breast cancer is ER+.

Example 32

A method of treating ovarian cancer comprising an administration to asubject in need thereof a solid form of RAD1901-2HCl according to any ofExamples 5-26.

Example 33

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising a peak, in terms of 2-theta, at 6.3 degrees 2θ±0.2 degree 2θat about relative humidity 0%.

Example 34

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising a peak, in terms of 2-theta, at 6.3 degrees 2θ±0.2 degree 2θand/or 12.5 degrees 2θ±0.2 degree 2θ at about relative humidity 0%.

Example 35

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least two peaks, in terms of 2-theta, selected from thegroup consisting of 6.3 degrees 2θ±0.2 degree 2θ, 12.5 degrees 2θ±0.2degree 2θ and 15.4 degrees 2θ±0.2 degree 2θ, at about relative humidity0%.

Example 36

A solid form of RAD1901-2HCl, having an X-ray powder diffraction patterncomprising at least three peaks, in terms of 2-theta, selected from thegroup consisting of 6.3 degrees 2θ±0.2 degree 2θ, 12.5 degrees 2θ±0.2degree 2θ, 15.4 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θand 13.4 degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.

Example 37

A solid form of RAD1901-2HCl having an X-ray powder diffraction patternsubstantially as shown in FIG. 5H at about relative humidity 0%.

Example 38

A pharmaceutical composition comprising a solid form according to anyone of Examples 32-37 and one or more pharmaceutically acceptableexcipients.

Example 39

A solid form of RAD1901-2HCl that is a hydrate.

Example 40

The solid form of RAD1901-2HCl of Example 39 that is a dihydrate.

Example 41

The solid form of Examples 39 or 40 having an X-ray powder diffractionpattern comprising a peak, in terms of 2-theta, at 5.8 degrees 2θ±0.2degree 2θ at about relative humidity 92%.

Example 42

The solid form of any of Examples 39-41 having an X-ray powderdiffraction pattern comprising a peak, in terms of 2-theta, at 5.8degrees 2θ±0.2 degree 2θ and/or 21.3 degrees 2θ±0.2 degree 2θ, at aboutrelative humidity 92%.

Example 43

The solid form of any of Examples 39-41 having an X-ray powderdiffraction pattern comprising at least two peaks, in terms of 2-theta,selected from the group consisting of 5.8 degrees 2θ±0.2 degree 2θ, 21.3degrees 2θ±0.2 degree 2θ and 24.8 degrees 2θ±0.2 degree 2θ, at aboutrelative humidity 92%.

Example 44

The solid form of any of Examples 39-41 having an X-ray powderdiffraction pattern comprising at least three peaks, in terms of2-theta, selected from the group consisting of 5.8 degrees 2θ±0.2 degree2θ, 21.3 degrees 2θ±0.2 degree 2θ, 24.8 degrees 2θ±0.2 degree 2θ, 23.3degrees 2θ±0.2 degree 2θ and 9.5 degrees 2θ±0.2 degree 2θ, at aboutrelative humidity 92%.

Example 45

The solid form of any of Examples 39-41 having an X-ray diffractionpattern comprising at least four peaks, in terms of 2-theta, selectedfrom the group consisting of 5.8 degrees 2θ±0.2 degree 2θ, 21.3 degrees2θ±0.2 degree 2θ, 24.8 degrees 2θ±0.2 degree 2θ, 23.3 degrees 2θ±0.2degree 2θ, 12.1 degrees 2θ±0.2 degree 2θ and 9.5 degrees 2θ±0.2 degree2θ, at about relative humidity 92%.

Example 46

A solid form of RAD1901-2HCl that is amorphous.

Example 47

A form of RAD1901-2HCl as an amorphous material in a dispersion matrix.

Example 48

A tablet comprising 400 mg amorphous RAD1901-2HCl dispersed into amatrix.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

The invention claimed is:
 1. A method of treating ovarian cancer,comprising administering to a subject in need thereof a solid form ofRAD1901-2HCl, having an X-ray powder diffraction pattern comprising apeak, in terms of 2-theta, at 7.1 degrees 2θ±0.2 degree 2θ at aboutrelative humidity 0%.
 2. The method of claim 1, wherein the solid formhas an X-ray powder diffraction pattern comprising peaks, in terms of2-theta, at 7.1 degrees 2θ±0.2 degree 2θ and 14.3 degrees 2θ±0.2 degree2θ at about relative humidity 0%.
 3. The method of claim 1, wherein thesolid form has an X-ray powder diffraction pattern further comprising atleast one peak, in terms of 2-theta, selected from the group consistingof 14.3 degrees 2θ±0.2 degree 2θ and 18.3 degrees 2θ±0.2 degree 2θ atabout relative humidity 0%.
 4. The method of claim 1, wherein the solidform has an X-ray powder diffraction pattern further comprising at leasttwo peaks, in terms of 2-theta, selected from the group consisting of14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8degrees 2θ±0.2 degree 2θ and 12.0 degrees 2θ±0.2 degree 2θ, at aboutrelative humidity 0%.
 5. The method of claim 1, wherein the solid formhas an X-ray powder diffraction pattern further comprising at leastthree peaks, in terms of 2-theta, selected from the group consisting of14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees2θ±0.2 degree 2θ and 18.9 degrees 2θ±0.2 degree 2θ, at about relativehumidity 0%.
 6. The method of claim 1, wherein the solid form has anX-ray powder diffraction pattern further comprising at least four peaks,in terms of 2-theta, selected from the group consisting of 14.3 degrees2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ,18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ and 11.0degrees 2θ±0.2 degree 2θ, at about relative humidity 0%.
 7. The methodof claim 1, wherein the solid form has an X-ray powder diffractionpattern further comprising at least four peaks, in terms of 2-theta,selected from the group consisting of 14.3 degrees 2θ±0.2 degree 2θ,18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ, 12.0degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9 degrees2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees 2θ±0.2degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relative humidity0%.
 8. The method of claim 1, wherein the solid form has an X-ray powderdiffraction pattern further comprising at least six peaks, in terms of2-theta, selected from the group consisting of 14.3 degrees 2θ±0.2degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees 2θ±0.2 degree 2θ,12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2 degree 2θ, 18.9degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ, 11.0 degrees2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, at about relativehumidity 0%.
 9. The method of claim 1, wherein the solid form has anX-ray powder diffraction pattern further comprising at least eight sevenpeaks, in terms of 2-theta, selected from the group consisting of 14.3degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ,11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, atabout relative humidity 0%.
 10. The method of claim 1, wherein the solidform has an X-ray powder diffraction pattern further comprising at leasteight peaks, in terms of 2-theta, selected from the group consisting of14.3 degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8degrees 2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees2θ±0.2 degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2degree 2θ, 11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree2θ, at about relative humidity 0%.
 11. The method of claim 1, whereinthe solid form has an X-ray powder diffraction pattern comprising thepeaks, in terms of 2-theta, of 7.1 degrees 2θ±0.2 degree 2θ, 14.3degrees 2θ±0.2 degree 2θ, 18.3 degrees 2θ±0.2 degree 2θ, 13.8 degrees2θ±0.2 degree 2θ, 12.0 degrees 2θ±0.2 degree 2θ, 25.1 degrees 2θ±0.2degree 2θ, 18.9 degrees 2θ±0.2 degree 2θ, 27.2 degrees 2θ±0.2 degree 2θ,11.0 degrees 2θ±0.2 degree 2θ and 16.2 degrees 2θ±0.2 degree 2θ, atabout relative humidity 0%.
 12. The method of claim 1, wherein the solidform has an X-ray powder diffraction pattern as shown in FIG. 4G atabout relative humidity 0%.
 13. The method of claim 1, wherein the solidform has a differential scanning calorimetry (DSC) thermogram comprisinga melting onset at 218.2° C. and an endothermic peak at 232.1° C. 14.The method of claim 13, wherein the solid form has a differentialscanning calorimetry (DSC) thermogram as shown in the bottom figure ofFIG.
 8. 15. The method of claim 1, wherein the solid form has athermogravimetric analysis (TGA) as shown in the top graph of FIG. 8.16. The method of claim 1, wherein said ovarian cancer is ER+.
 17. Themethod of claim 16, wherein the ovarian cancer is a resistant ER-drivencancer that progressed after endocrinological treatment, wherein theendocrinological treatment comprises administration of a drug selectedfrom a Selective Estrogen Receptor Degrader (SERD), an aromataseinhibitor, a selective estrogen receptor modulator (SERM), a HumanEpidermal Growth Factor Receptor 2 (Her2) inhibitor, a chemo therapeuticagent, a cdk4/6 inhibitor, an m-TOR inhibitor, or rituximab.
 18. Themethod of claim 17, wherein the SERD is selected from fulvestrant,17β-[2-[4-[(diethylamino)methyl]-2-methoxyphenoxy]ethyl]-7α-methylestra-1,3,5(10)-trien-3-ol(TAS-108BU or SR16234),11β-Fluoro-7α-(14,14,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17β-diol(ZK191703),(11β,17β)-11-[4-[[5-[(4,4,5,5,5-Pentafluoropentyl)sulfonyl]-pentyl]oxy]phenylestra-1,3,5(10)-triene-3,17-diol(RU58668), Brilanestrant (GDC-0810 or ARN-810), Etacstil (GW5638 orDPC974),(S)-2-(4-(2-(3-(fluoromethyl)-azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol(SRN-927), and(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (AZD9496); the aromatase inhibitor is selected from anastrozole,exemestane, and letrozole; the selective estrogen receptor modulator isselected from tamoxifen, raloxifene, lasofoxifene, and toremifene; theHer2 inhibitor is selected from trastuzumab, lapatinib, ado-trastuzumabemtansine, and pertuzumab; the chemo therapeutic agent is selected fromabraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil,ellence, fluorouracil, gemzar, helaven, Ixempra, methotrexate,mitomycin, micoxantrone, navelbine, taxol, taxotere, thiotepa,vincristine, and xeloda; and the angiogenesis inhibitor is bevacizumab.19. The method of claim 16, wherein the ovarian cancer is a resistantER-driven cancer that progress after endocrinological treatment, whereinthe ovarian cancer has one or more mutant ER binding domains comprisingone or more mutations selected from the group consisting of Y537X₁wherein X₁ is S, N, or C, D538G, L536X₂ wherein X₂ is R or Q, P535H,V534E, S463P, V392I, and E380Q, or a combination thereof.